Rare Pulmonology News

Disease Profile

Phosphoribosylpyrophosphate synthetase superactivity

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

#N/A

ICD-10

#N/A

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

no.svg

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

no.svg

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

no.svg

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

no.svg

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

no.svg

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

no.svg

Not applicable

no.svg

Other names (AKA)

PRPP synthetase superactivity; PRPS1 superactivity

Categories

Metabolic disorders

Summary

The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs.
orphanet

Orpha Number: 3222

Definition
Phosphoribosylpyrophosphate (PRPP) synthetase superactivity is an X-linked disorder of purine metabolism associated with hyperuricemia and hyperuricosuria, comprised of two forms: an early-onset severe form characterized by gout, urolithiasis, and neurodevelopmental anomalies (severe PRPP synthetase superactivity) and a mild late-onset form with no neurologic involvement (mild PRPP synthetase superactivity) (see these terms).

Epidemiology
PRPP synthetase superactivity is a rare disorder with less than 30 families described in the literature to date.

Clinical description
PRPP synthetase superactivity affects mainly males. Most individuals (approximately 75%) are affected by the milder form, which manifests in late adolescence or early adulthood, usually with uric acid crystalluria and (kidney and/or bladder) urinary stones, followed by the development of gouty arthritis and eventually renal failure as a result of obstructive uropathy from uric acid crystal deposition. The severe form usually starts from infancy or early childhood and shares the same clinical features with the mild form but also shows neurologic impairment, mainly sensorineural hearing loss, hypotonia, ataxia, developmental delay, and /or intellectual disability. Heterozygous carrier women are either asymptomatic or display mild metabolic and neurologic symptoms.

Etiology
The disease is due to overactivity of ribose-phosphate pyrophosphokinase 1 (PRS-I), an enzyme that catalyzes the synthesis of PRPP, a cofactor involved in the synthesis of purine and pyrimidine nucleotides. PRS-I overactivity results in the overproduction of purine nucleotides and uric acid (a waste product of purine breakdown). In the severe form, PRS-I overactivity is due to gain-of-function point mutations in the open reading frame of the PRSP1 gene (Xq22.3) encoding PRS-I, that lead to defective allosteric control of PRS-I isoform activity. The exact molecular mechanism leading to the mild form is not yet well understood as no mutations have been found in PRSP1, but it seems to be linked to increased rates of PRSP1 transcription.

Diagnostic methods
In both forms, diagnosis is based on blood and urine analysis showing hyperuricemia, hyperuricosuria, and uric acid crystalluria. Diagnosis is confirmed by PRS enzyme assay showing increased PRS-I activity in fibroblasts, lymphoblasts, and erythrocytes. Molecular genetic testing also confirms the diagnosis in the severe forms.

Differential diagnosis
Differential diagnosis includes hypoxanthineguanine phosphoribosyltransferase deficiency and psychomotor retardation due to S-adenosylhomocysteine hydrolase (AHCY) deficiency (see these terms).

Antenatal diagnosis
Carrier testing for at-risk relatives and prenatal testing in male fetuses are possible if the mutation has been identified in the family.

Genetic counseling
PRPP synthetase superactivity is an X-linked recessive disorder with complete penetrance. An affected mother has a 50% chance of transmitting the disease to any of her offspring; an affected father transmits the mutation only to his daughters. De novo PRSP1 mutations have also been reported.

Management and treatment
Treatment of uric acid overproduction with xanthine oxidase inhibitors like allopurinol or febuxostat successfully reverses or prevents the consequences of hyperuricemia and hyperuricosuria. A low-purine and low-fructose diet along with regular surveillance of serum urate concentration is essential. Alcalinisation of urine is recommended in order to avoid the formation of kidney stones. For patients with the severe form, regular audiometric and neurologic evaluations are also recommended.

Prognosis
The prognosis is uncertain in the severe form of the disease. Severe gout can lead to renal impairment, if not properly treated.

Visit the Orphanet disease page for more resources.

Symptoms

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Ataxia
0001251
Hyperuricemia
High blood uric acid level
0002149
Sensorineural hearing impairment
0000407
30%-79% of people have these symptoms
Abnormal aortic morphology
0001679
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Muscular hypotonia
Low or weak muscle tone
0001252
Neurological speech impairment
Speech disorder
Speech impairment
Speech impediment

[ more ]

0002167
Renal insufficiency
Renal failure
Renal failure in adulthood

[ more ]

0000083
5%-29% of people have these symptoms
Arrhythmia
Abnormal heart rate
Heart rhythm disorders
Irregular heart beat
Irregular heartbeat

[ more ]

0011675
Cardiomyopathy
Disease of the heart muscle
0001638
Hypertension
0000822
Strabismus
Cross-eyed
Squint
Squint eyes

[ more ]

0000486
Percent of people who have these symptoms is not available through HPO
Generalized hypotonia
Decreased muscle tone
Low muscle tone

[ more ]

0001290
Gout
0001997
Hyperuricosuria
High urine uric acid level
0003149
Increased phosphoribosylpyrophosphate synthetase level
0003240
Motor delay
0001270
Uric acid nephrolithiasis
Uric acid stones
0000791
X-linked recessive inheritance
0001419

Learn more

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

In-Depth Information

  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Phosphoribosylpyrophosphate synthetase superactivity. Click on the link to view a sample search on this topic.